RESUMEN
BACKGROUND AND PURPOSE: Retigabine is a recently approved antiepileptic agent which activates Kv7.2-7.5 potassium channels. It is emerging that these channels have an important role in vascular regulation, but the vascular effects of retigabine in the conscious state are unknown. Hence, in the present study we assessed the regional haemodynamic responses to retigabine in conscious rats. EXPERIMENTAL APPROACH: Male Sprague Dawley rats were chronically instrumented with pulsed Doppler flow probes to measure regional haemodynamic responses to retigabine under control conditions and during acute hypertension induced by infusion of angiotensin II and arginine vasopressin. Further experiments were performed, using the ß-adrenoceptor antagonists CGP 20712A, ICI 118551 and propranolol, to elucidate the roles of ß-adrenoceptors in the responses to retigabine in vivo and in vitro. KEY RESULTS: Under normotensive conditions, retigabine induced dose-dependent hypotension and hindquarters vasodilatation, with small, transient renal and mesenteric vasodilatations. In the acutely hypertensive state, the renal and mesenteric, but not hindquarters, vasodilatations were enhanced. The response of the hindquarters vascular bed to retigabine was mediated, in part, by ß2-adrenoceptors. However, in vitro experiments confirmed that retigabine did not act as a ß-adrenoceptor agonist. CONCLUSIONS AND IMPLICATIONS: We demonstrated that retigabine causes regionally specific vasodilatations, which are different under normotensive and hypertensive conditions, and are, in part, mediated by ß2-adrenoceptors in some vascular beds but not in others. These results broadly support previous findings and further indicate that Kv7 channels are a potential therapeutic target for the treatment of vascular diseases associated with inappropriate vasoconstriction.
Asunto(s)
Antihipertensivos/uso terapéutico , Carbamatos/uso terapéutico , Circulación Coronaria/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Canales de Potasio KCNQ/agonistas , Canal de Potasio KCNQ2/agonistas , Moduladores del Transporte de Membrana/uso terapéutico , Fenilendiaminas/uso terapéutico , Agonistas de Receptores Adrenérgicos beta 2/administración & dosificación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/farmacología , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Agonistas Adrenérgicos beta/farmacología , Agonistas Adrenérgicos beta/uso terapéutico , Animales , Antihipertensivos/administración & dosificación , Antihipertensivos/efectos adversos , Antihipertensivos/farmacología , Arritmias Cardíacas/inducido químicamente , Células CHO , Carbamatos/administración & dosificación , Carbamatos/efectos adversos , Carbamatos/farmacología , Cricetulus , Relación Dosis-Respuesta a Droga , Humanos , Canales de Potasio KCNQ/metabolismo , Canal de Potasio KCNQ2/metabolismo , Masculino , Moduladores del Transporte de Membrana/administración & dosificación , Moduladores del Transporte de Membrana/efectos adversos , Moduladores del Transporte de Membrana/farmacología , Fenilendiaminas/administración & dosificación , Fenilendiaminas/efectos adversos , Fenilendiaminas/farmacología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/genética , Receptores Adrenérgicos beta 2/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Vasodilatación/efectos de los fármacosRESUMEN
Vascular endothelial growth factor-A is widely regarded as the principal stimulator of angiogenesis required for tumour growth. VEGF is generated as multiple isoforms of two families, the pro-angiogenic family generated by proximal splice site selection in the terminal exon, termed VEGFxxx, and the anti-angiogenic family formed by distal splice site selection in the terminal exon, termed VEGFxxxb, where xxx is the amino acid number. The most studied isoforms, VEGF165 and VEGF165b have been shown to be present in tumour and normal tissues respectively. VEGF165b has been shown to inhibit VEGF- and hypoxia-induced angiogenesis, and VEGF-induced cell migration and proliferation in vitro. Here we show that overexpression of VEGF165b by tumour cells inhibits the growth of prostate carcinoma, Ewing's sarcoma and renal cell carcinoma in xenografted mouse tumour models. Moreover, VEGF165b overexpression inhibited tumour cell-mediated migration and proliferation of endothelial cells. These data show that overexpression of VEGF165b can inhibit growth of multiple tumour types in vivo indicating that VEGF165b has potential as an anti-angiogenic, anti-tumour strategy in a number of different tumour types, either by control of VEGF165b expression by regulation of splicing, overexpression of VEGF165b, or therapeutic delivery of VEGF165b to tumours.
Asunto(s)
Neoplasias/patología , Factor A de Crecimiento Endotelial Vascular/farmacología , Empalme Alternativo , Animales , Carcinoma de Células Renales/patología , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Regulación hacia Abajo , Células Endoteliales/efectos de los fármacos , Masculino , Ratones , Ratones Desnudos , Trasplante de Neoplasias , Neoplasias/irrigación sanguínea , Neovascularización Patológica , Próstata/citología , Próstata/efectos de los fármacos , Neoplasias de la Próstata/patología , Isoformas de Proteínas , Sarcoma de Ewing/patología , Transfección , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Recent policy initiatives threaten to reduce the rehabilitative mission of the juvenile court or eliminate the court entirely. This article lays out a framework for an empirical assessment of these developments. It first evaluates the available and potential empirical support for three hypotheses about juveniles that might justify maintaining a separate, rehabilitation-oriented juvenile justice system: the hypotheses that, compared to adults, juveniles are more treatable, less culpable, and less deterrable. On the assumption that the continued existence of a rehabilitation-oriented juvenile court can be justified, it then provides suggestions as to how existing intervention strategies for juveniles could benefit from research attention to several substantive and methodological issues. These include refining outcome criteria and sampling strategies, matching offender and program characteristics, reexamining intervention efficacy, and focusing on decision makers and resource allocations.
Asunto(s)
Conducta del Adolescente/psicología , Ciencias de la Conducta/organización & administración , Política de Salud/legislación & jurisprudencia , Delincuencia Juvenil/legislación & jurisprudencia , Delincuencia Juvenil/psicología , Psicología del Adolescente/legislación & jurisprudencia , Investigación/organización & administración , Adolescente , Política de Salud/tendencias , Humanos , Delincuencia Juvenil/prevención & control , Delincuencia Juvenil/rehabilitación , Evaluación de Necesidades , Estados UnidosRESUMEN
Psychology can and should be at the forefront of participation in social, community, and preventive interventions. This chapter focuses on selective topics under two general areas: violence as a public health problem and health promotion/competence promotion across the life span. Under violence prevention, discussion of violence against women, youth violence, and child maltreatment are the focal points. Under health and competence promotion, attention is paid to the prevention of substance abuse and HIV/AIDS. We highlight a few significant theoretical and empirical contributions, especially from the field of community/prevention psychology. The chapter includes a brief overview of diversity issues, which are integral to a comprehensive discussion of these prevention efforts. We argue that the field should extend its role in social action while emphasizing the critical importance of rigorous research as a component of future interventions.
Asunto(s)
Promoción de la Salud , Trastornos Mentales/prevención & control , Prevención Primaria , Trastornos Relacionados con Sustancias/prevención & control , Violencia/prevención & control , Adolescente , Adulto , Niño , Preescolar , Servicios Comunitarios de Salud Mental/tendencias , Etnicidad/educación , Femenino , Infecciones por VIH/prevención & control , Infecciones por VIH/psicología , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Gestión de Riesgos , Apoyo SocialRESUMEN
To determine whether regional wall motion abnormalities exist or contribute to left ventricular dysfunction, we obtained two-dimensional echocardiograms in 12 athletes before (baseline), immediately after (race finish), and 1 day after (recovery) the Hawaii Ironman Triathlon (a 3.9-km swimming, 180.2-km bicycling, and 42.2-km running event). Left ventricular short-axis and apical four-chamber views were computer digitized and divided into six segments, and radial chord shortening and area ejection fraction were calculated. Global ejection fraction fell at race finish (51% versus 46%, p less than 0.05) but recovered by 1 day (54%, p less than 0.01 by repeated-measures analysis of variance). With the apical four-chamber view, midseptal and apical-septal motion were reduced at race finish but returned to baseline during recovery (midseptal radial chord shortening: 21%, 8%, 22%; apical-septal radial chord shortening: 27%, 12%, 25%; midseptal area ejection fraction: 39%, 30%, 40%; apical-septal area ejection fraction: 44% baseline, 33% race finish, 43% recovery; all p less than 0.01). In contrast, with the parasternal short-axis view, wall motion did not change at race finish but tended to be elevated during recovery and became significant for anteroseptal motion (radial chord shortening: 29%, 30%, 36%; area ejection fraction: 49% baseline, 51% race finish, 58% recovery; both p less than 0.05). Lateral wall motion was unchanged. In addition, an index of septal curvature was calculated using the ratio of the septal-lateral wall minor axis to the perpendicular anteroposterior minor axis. At all three data collections, this ratio remained close to 1.0 at end systole and end diastole.(ABSTRACT TRUNCATED AT 250 WORDS)